The goal of this proposal is to define the role of the a21 integrin in tumor metastasis, with specific interest on the interplay between malignant mammary epithelial cells and the tumor microenvironment. Integrin-mediated interactions between tumor cells and their microenvironment are required for tumor progression and metastasis. Our earliest data derived from human pathological specimens demonstrated that the a21 integrin was highly expressed on normal epithelial cells but was diminished or lost in cancer in a manner that correlated with cancer progression. We now present new and exciting preliminary data that lack of the a21 integrin expression promotes tumor metastasis in an in vivo model of spontaneous breast cancer. Although primary tumor incidence and latency were similar, metastases were twice as frequent in transgenic MMTV-c-neu mice lacking the a21 integrin relative to wild type MMTV-c-neu littermate controls. Thus, the a21 integrin may function as a metastasis suppressor gene that alters the rate of metastasis but not tumor initiation. Metastatic disease is not solely dependent on the malignant epithelial cell, but is equally influenced by the tumor microenvironment. When wild type and a2-null were injected intravenously with Lewis Lung carcinoma cells, the a2-null animals harbored significantly increased metastatic disease. These data from the intravenous injection of tumor cells suggest that increased metastasis is a consequence of host factors influencing the later steps of the tumor metastatic process. We cannot exclude additional contributions from the a2-null tumor cells in the spontaneous metastasis model. Based on these data we propose the following hypotheses and aims to address the hypotheses: 1) The a21 integrin is a metastasis suppressor gene and alters tumor progression and the metastatic phenotype; 2) the a21 integrin modifies the tumor micro-environment to serve as a metastasis efficiency modifier gene. AIM #1: To define the independent or cooperative contributions mediated by the a21 integrin when expressed by tumor cells alone, by the tumor microenvironment alone, or by both tumor and microenvironment that leads to suppression of metastasis. Focus - the interaction of the tumor cells and the microenvironment. AIM #2: To define the role and determine the molecular mechanisms by which the a21 integrin expression by the tumor cells regulates tumor progression. Focus - the tumor cells. AIM #3: To determine the role of the a21 integrin modifies the host microenvironment to suppress tumor metastasis. This aim will focus specifically on the lung and the steps of intravasation, cell survival, arrest and colonization. Focus - the microenvironment of the metastatic site in the lung. PUBLIC HEALTH RELEVANCE: Metastasis is the main cause of cancer death. We have identified a protein that may suppress the incidence and severity of breast cancer metastasis. This proposal will evaluate the way in which this protein suppresses tumor metastasis.